Modulation of the tumor microenvironment with probiotic therapies
用益生菌疗法调节肿瘤微环境
基本信息
- 批准号:10380671
- 负责人:
- 金额:$ 56.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-03 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:4T1AddressAdjuvantAdverse effectsAnaerobic BacteriaAntibioticsAntibodiesAntigen PresentationAntitumor ResponseAutomobile DrivingBacteriaBar CodesBiodistributionBlood CirculationBone TissueBreast Cancer ModelBreast Cancer cell lineCD47 geneCTLA4 geneCellsCessation of lifeClinical TrialsCombined Modality TherapyCytolysisCytotoxic T-LymphocytesDefectDiseaseDistant MetastasisDoseEngineered ProbioticsEngineeringEnvironmentEscherichia coliFaceFutureGeneticGenetic TranscriptionGoalsGrowthHomingImmuneImmune checkpoint inhibitorImmune systemImmunityImmunologicsImmunotherapeutic agentImmunotherapyIn complete remissionInflammatoryInjectionsIntelligenceInterleukin-12IntravenousKineticsKnock-outLesionLibrariesLipopolysaccharidesLuciferasesLymphomaMalignant NeoplasmsMeasurementMediatingMedicineMetastatic Neoplasm to the LiverMetastatic breast cancerModelingMolecularMonitorMusNeoplasm MetastasisNeutrophil InfiltrationOralOrganPathway interactionsPatient-Focused OutcomesPatientsPeptide/MHC ComplexPhagocytesPrimary LesionPrimary NeoplasmProbioticsProductionPropertyReportingSafetySoft tissue sarcomaSolid NeoplasmSourceSpecificityStainsStreptococcusT cell responseT-LymphocyteTherapeuticToxic effectTranslationsTropismTumor AntigensTumor ImmunityTumor-Infiltrating LymphocytesUnresectableWomanWorkantigen-specific T cellsbasecancer immunotherapycancer therapychemotherapycomplement systemcytokinedelivery vehicledensitydesignhost-microbe interactionsimmunogenicityimprovedin vivo imaging systeminnovationknockout genemalignant breast neoplasmmicrobialmortalitymouse modelmutantnanobodiesneoantigensnovelpre-clinicalpreclinical developmentpreventprobiotic therapyprogrammed cell death ligand 1programsside effectsuccesssynthetic biologysystemic toxicitytargeted treatmenttranscription factortriple-negative invasive breast carcinomatumortumor microenvironment
项目摘要
Recent advances in cancer immunotherapy have provided promising treatment options for patients with triple-negative
breast cancer (TNBC). Despite overall success in treating these malignancies, immunotherapeutic approaches
face a number of unique challenges: (1) dose limitation due to off-target side effects, (2) additive toxicity
of combination therapies, (3) and relatively low immunogenicity of breast cancer. To overcome these limitations,
this proposal seeks to engineer probiotic strains of bacteria that selectively colonize breast cancer and locally
release immunotherapeutics. The ultimate goal is to elicit more robust and diversified antitumor T cell immunity
and promote the clearance of colonized primary and metastatic breast cancer lesions and systemically growing
breast cancer-derived foci. The accompanying project will first focus on deciphering mechanisms that define the
intratumoral tropism of the probiotic strain E. coli Nissle 1917 (EcN) by using antibody-mediated depletion approaches
and targeted genetic knockouts to pinpoint host immunological pathways that regulate tumor-specific
growth. Using synthetic biology approaches, EcN will then be engineered to stably express and release checkpoint
inhibitor nanobodies targeting CD47, PD-L1, and CTLA-4 locally inside of tumors. Pro-inflammatory cytokines
will additionally be expressed to promote antigen presentation and enhance cytotoxic T cell responses.
The primary innovations of this proposal are in the combined approach of both developing a better understanding
of probiotic colonization of tumors, along with engineering probiotics as an immunotherapeutic delivery vector.
Specifically, this approach has several advantages over current therapeutic strategies, including: (1) identification
of novel EcN host strains and mechanistic understanding of their tumor colonization for further improvements
in engineered therapies, (2) tumor-specific production of immunotherapeutics, (3) bacteria lysis that leads to
effective release of novel immunotherapeutics and lipopolysaccharides (LPS) adjuvant, and (4) local delivery of
novel immunotherapeutic combinations that are toxic to deliver systemically. This work seeks to overcome current
limitations of immunotherapies, by providing a targeted vehicle to locally deliver immunotherapies that stimulate
antitumor immunity while preventing systemic toxicity and mitigating immune-related adverse effects.
癌症免疫治疗的最新进展为三阴性患者提供了有希望的治疗选择
乳腺癌(TNBC)。尽管这些恶性肿瘤的治疗总体上取得了成功,但免疫治疗方法
面临一些独特的挑战:(1)非靶标副作用造成的剂量限制,(2)相加毒性
联合治疗;(3)乳腺癌免疫原性较低。为了克服这些限制,
这项提议寻求改造益生菌菌株,选择性地定植于乳腺癌和局部
释放免疫疗法。最终目标是诱导更强大和多样化的抗肿瘤T细胞免疫
并促进原发癌和转移性乳腺癌结缔组织的清除和系统性生长
乳腺癌衍生的病灶。随之而来的项目将首先专注于定义
用抗体介导的耗竭方法研究益生菌E.coliNissle 1917(ECN)的瘤内趋向性
和定向基因敲除,以确定调节肿瘤特异性的宿主免疫途径
成长。使用合成生物学方法,ECN将被设计成稳定表达和释放检查点
肿瘤内局部靶向CD47、PD-L1和CTLA-4的抑制物纳米体。促炎细胞因子
将额外表达以促进抗原递呈和增强细胞毒性T细胞反应。
这项建议的主要创新之处在于结合两种方法发展了更好的理解
益生菌对肿瘤的定植,以及工程益生菌作为免疫治疗递送载体。
具体地说,这种方法比目前的治疗策略有几个优点,包括:(1)识别
新的ECN宿主株及其肿瘤定植机制的研究
在工程疗法中,(2)肿瘤特异性免疫疗法的产生,(3)导致
新型免疫疗法和脂多糖佐剂的有效释放,以及(4)局部递送
具有全身毒性的新型免疫治疗组合。这项工作旨在克服当前的
免疫疗法的局限性,通过提供一个有针对性的载体来在当地提供免疫疗法,以刺激
抗肿瘤免疫,同时预防全身毒性,减轻免疫相关不良反应。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Nicholas Arpaia其他文献
Nicholas Arpaia的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Nicholas Arpaia', 18)}}的其他基金
Programmable encapsulation systems to improve delivery of therapeutic bacteria
可编程封装系统可改善治疗性细菌的递送
- 批准号:
10639259 - 财政年份:2023
- 资助金额:
$ 56.13万 - 项目类别:
Treating colon cancer by regulating intestinal immunity through microbial metabolism
通过微生物代谢调节肠道免疫治疗结肠癌
- 批准号:
10189065 - 财政年份:2021
- 资助金额:
$ 56.13万 - 项目类别:
Treating colon cancer by regulating intestinal immunity through microbial metabolism
通过微生物代谢调节肠道免疫治疗结肠癌
- 批准号:
10618990 - 财政年份:2021
- 资助金额:
$ 56.13万 - 项目类别:
Treating colon cancer by regulating intestinal immunity through microbial metabolism
通过微生物代谢调节肠道免疫治疗结肠癌
- 批准号:
10410442 - 财政年份:2021
- 资助金额:
$ 56.13万 - 项目类别:
Engineering immunotherapeutic probiotics to mitigate irAE
工程免疫治疗益生菌以减轻 irAE
- 批准号:
10556326 - 财政年份:2020
- 资助金额:
$ 56.13万 - 项目类别:
Modulation of the tumor microenvironment with probiotic therapies
用益生菌疗法调节肿瘤微环境
- 批准号:
10737757 - 财政年份:2020
- 资助金额:
$ 56.13万 - 项目类别:
Lung leukocytes promote alveolar epithelial regeneration after severe injury
肺白细胞促进严重损伤后肺泡上皮再生
- 批准号:
10666350 - 财政年份:2020
- 资助金额:
$ 56.13万 - 项目类别:
Engineering immunotherapeutic probiotics to mitigate irAE
工程免疫治疗益生菌以减轻 irAE
- 批准号:
9921971 - 财政年份:2020
- 资助金额:
$ 56.13万 - 项目类别:
Lung leukocytes promote alveolar epithelial regeneration after severe injury
肺白细胞促进严重损伤后肺泡上皮再生
- 批准号:
9977404 - 财政年份:2020
- 资助金额:
$ 56.13万 - 项目类别:
Lung leukocytes promote alveolar epithelial regeneration after severe injury
肺白细胞促进严重损伤后肺泡上皮再生
- 批准号:
10225703 - 财政年份:2020
- 资助金额:
$ 56.13万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 56.13万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 56.13万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 56.13万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 56.13万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 56.13万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 56.13万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 56.13万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 56.13万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 56.13万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 56.13万 - 项目类别:
Research Grant